rs147700427

chr17-44007690-C-Gchr17-44007690-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153006.3(NAGS):c.1368C>G(p.Ser456=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,604,718 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S456S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: NAGS NM_153006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.48

Genes affected

NAGS (HGNC:17996): (N-acetylglutamate synthase) The N-acetylglutamate synthase gene encodes a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme-A. NAG is a cofactor of carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle in mammals. This gene may regulate ureagenesis by altering NAG availability and, thereby, CPSI activity. Deficiencies in N-acetylglutamate synthase have been associated with hyperammonemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-44007690-C-G is Benign according to our data. Variant chr17-44007690-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 384582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00182 (277/152296) while in subpopulation NFE AF= 0.00297 (202/68024). AF 95% confidence interval is 0.00263. There are 0 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGS	NM_153006.3	c.1368C>G	p.Ser456=	synonymous_variant	6/7	ENST00000293404.8
NAGS	XM_011524439.2	c.870C>G	p.Ser290=	synonymous_variant	6/7
NAGS	XM_011524438.2	c.1268+196C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGS	ENST00000293404.8	c.1368C>G	p.Ser456=	synonymous_variant	6/7	1	NM_153006.3	P1
NAGS	ENST00000589767.1	c.1299C>G	p.Ser433=	synonymous_variant	6/7	2
NAGS	ENST00000592915.1	n.1256C>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00170 AC: 393 AN: 231746 Hom.: 3 AF XY: 0.00164 AC XY: 206 AN XY: 125602

Gnomad AFR exome AF: 0.000422

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000563

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00282 AC: 4090 AN: 1452422 Hom.: 13 Cov.: 30 AF XY: 0.00271 AC XY: 1955 AN XY: 721544

Gnomad4 AFR exome AF: 0.000451

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000851

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000663

Gnomad4 FIN exome AF: 0.000495

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74468

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperammonemia, type III Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NAGS: BP4, BP7, BS2 -

NAGS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	7.7
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147700427; hg19: chr17-42085058;